Diffuse large B-cell lymphoma (DLBCL) accounts for about 25% of all lymphoma cases. [1]. Subtypes of DLBCL identified by gene expression profiling include germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL and primary mediastinal B-cell lymphoma (PMBL) [2,3]. Patients with the GCB subtype have a significantly better overall survival compared to those with the ABC subtype. [2,3]
ABC-DLBCL is characterized by its reliance on the oncogenic activation of the NF-κB pathway. [4] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) functions in an essential role in NF-κB signaling downstream of T-cell receptors (TCR) and B-cell receptors (BCR) [5]. MALT1 has also been shown to facilitate lymphocyte proliferation, activation, and cytokine production. [6,7] In NF-κB signaling, MALT1 functions as a scaffold protein and forms a complex, referred to as the CBM complex, with caspase recruitment domain family member 11 (CARD11) and B-cell lymphoma 10 (B-cell 10). Through a mechanism mediated by ubiquination of the CBM complex, multiple downstream NF-κB signals are activated to ultimately induce proteasomal degradation of IκBα and release NF-κB for nuclear translocation. [5]
In addition to the scaffold function, MALT1 contains a caspase-like domain with proteolytic activity for several important substrates in lymphocyte regulation. MALT1 is a paracaspase, which cleaves after an arginine or lysine residues instead of an aspartate as in caspases. [8] Known peptide substrates of MALT1, or fusion protein API2-MALT1, include A20, CYLD, Bcl10, RelB, regnase-1, roquin-1, NIK, LIMA1α, and MALT1. [8-16] API2-MALT1 results from a t(11;18)(q21;q21) translocation, and is detected in up to 55% of patents with MALT associated lymphomas. [17] Cleavage of these peptides by MALT1 results in inactivation of the peptides resulting in a range of effects, including enhancing NF-κB activation, enhancing B-cell adhesion to fibronectin, and promoting cytokine expression and secretion. Through these and other mechanisms the paracaspase activity of MALT1 promotes cell proliferation and survival in lymphomas and autoimmune diseases. [5] Due in particular to the high chemo-resistance and low survival rates associated with ABC-DLBCL there is a need from improved therapeutic agents that target lymphocyte signaling and proliferation pathways such as those mediated by MALT1 paracaspase activity.